LRRK2 Data and Development
Halia was founded on the discovery of a rare genetic variant providing protection to Alzheimer’s disease
- Halia has identified a lead compound to inhibit LRRK2 optimized to reduce phosphorylated Rab10 levels
- Mutations in the LRRK2 gene have been identified as the most common genetic cause of familial Parkinson’s disease
- However LRRK2 mutations have also been implicated in the development of other neurodegenerative disorders: Alzheimer’s disease and Amyotrophic lateral sclerosis (ALS)
- LRRK2-RAB10 signaling pathway causes an overproduction of Aβ
- Formation of Aβ allows the amyloid plaques, which define a primary component of AD pathology, to be
formed - LRRK2 also mediates RAB10 activation by phosphorylation at Thr73, which may represent a pathologic feature in the brains of AD patients
The APOE4 variant increases lifetime risk for Alzheimer’s disease
APOE4 gene and risk of developing Alzheimer’s disease
%
No Copies of APOE4 Gene:
250 million Americans lifetime risk of developing Alzheimer’s Disease
%
1 copy of APOE4:
70 million Americans lifetime risk of developing Alzheimer’s Disease
%
2 Copies of APOE4 Gene:
7 million Americans lifetime risk of developing Alzheimer’s Disease
- Having one APOE4 polymorphism increases the risk of getting Alzheimer’s disease threefold
- Having two copies increases the risk of getting Alzheimer’s disease twelvefold
LRRK2 Activates RAB10 in Neurological Disorders
The LRRK2-RAB10 Pathway
What is RAB10:
RAB10 is a small GTPase protein that is known to play a critical role in the endoplasmic reticulum, neuronal morphology, dendritic growth and lysosomal function. A functional variant in RAB10 has been identified as impacting risk for Alzheimer’s Disease
How is RAB10 affected by LRRK2:
LRRK2 phosphorylates RAB10 at a specific site, referred to as threonine 73 (Thr37). Clinical research increasingly points to this
phosphorylation activating RAB10, regulating vesicle trafficking within cells
How does a defect in LRRK2 impact the pathology of Alzheimer’s Disease:
The LRRK2-RAB10 signaling pathway has been linked to an overproduction of Aβ peptides, an essential component of the
pathogenesis of Alzheimer’s Disease, creating a promising set of therapeutic targets for Alzheimer’s Disease intervention
RAB10 inhibition represents a promising case for therapeutic intervention in AD
LRRK2 inhibition reduces neuroinflammation and promotes neuroprotection
Inhibition of LRRK2’s inflammatory signaling
- Microglia
LRRK2 inhibitors block overexpression in the brain’s
immune cells (microglia) leading to decreased
production of pro-inflammatory molecules, which
dampens the inflammatory cascade and protecting
surrounding neurons - Neurons
LRRK2 inhibitors disrupt the production of
inflammatory mediators caused by interaction with
proteins like NF-kB and can protect neurons from
damage - RAB10 and LRRK2 interaction
RAB10 plays a critical role in LRRK2-mediated
neurotoxicity by dysregulating the autophagy-
lysosome pathway and NLRP3 inflammasome in
microglia – LRRK2 inhibition would mitigate this